We read with interest the series of patients described by Ba-Abbad et al. [1]. Whilst biallelic truncating CDHR1 variants result in cone-rod or rod-cone dystrophies—consistent with the Cdhr1−/− knockout mouse [2]—it is intriguing that certain biallelic splice or missense variants in CDHR1 may result in late-onset macular dystrophy.

Variants in CDHR1 described in association with late-onset macular dystrophy [1] appear to affect the ectodomains of CDHR1. Although the six extracellular cadherin repeats form the longest part of the protein, they are the most conserved, suggesting an important biological function [3]. Ultrastructural analysis with immunogold labelling of CDHR1 in murine retinae identified that evaginating, nascent discs at the base of the photoreceptor outer segments form CDHR1-based connections with the inner segments [4]. Formed from the ectodomains of CDHR1, the contacts are lost as outer segment discs mature. This physical separation occurs through proteolytic cleavage of the CDHR1 ectodomain [3]. Non-truncating CDHR1 variants affecting the ectodomain may interfere with its proteolytic cleavage, or attachments to the inner segment, thereby resulting in dystrophic outer segments without widespread photoreceptor degeneration seen with biallelic truncating variants.

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